BCH210H1 Lecture Notes - Lecture 38: Hmg-Coa Reductase, Acetyl-Coa, Cholesteryl Ester

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BCH210 Lecture 32 Lipoproteins
Cholesterol
- Very hydrophobic
- Has one hydroxyl polar group
- Lots of carbon chains coming from acetyl CoA which make the overall molecule very
hydrophobic
Cholesterol Synthesis in the liver
- Cholesterol is needed for membrane biochemistry and as a precursor for hormones, bile
salts and vitamin D3 production
o Bile salts are needed to solubilize dietary lipids
- Cholesterol is made from acetyl CoA in the liver cytoplasm using carbons from fat /
protein / carbohydrate catabolism
- HMG-CoA reductase is the major point of regulation
- HMG-CoA reductase can be inactivated by phosphorylating it by cAMP-dependent
kinases
- Statins also target HMG-CoA reductase via competitive inhibition
Cholesterol synthetic pathway
- Cholesterol synthesis is an anabolic pathway, so it requires energy
- Lots of acetyl CoA is required to produce cholesterol
- HMG-CoA reductase uses NADPH to form mevalonate in the cytoplasm
- ATP is required to form a 5-carbon isoprene unit and many of these combine to form
squalene
- Additional steps lead to ring cyclization by enzymes found at the ER membrane,
producing cholesterol
Statins are competitive inhibitors
- Statins have a very similar structure to mevalonate
- Drugs can bind to the active site of the enzyme and interact with the same amino acids
- The extra chemical group on statin prevents catalysis from taking place
- Competitive inhibition can be overcome by excess substrate which competes for binding
and the enzyme remains active
Cholesterol modification
- You can add an acyl chain to the polar group to form an even more hydrophobic
molecule known as cholesterol ester
- This acyl chain is important for the distribution of cholesterol
- Cholesterol is normally found on the membrane of lipoproteins, but cholesterol ester is
transported via lipoproteins in the inside
Lipoproteins and cholesterol
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